Interleukin-15 stimulates macrophages to activate CD4+ T cells: a role in the pathogenesis of rheumatoid arthritis?

Immunology. 2009 Jan;126(1):63-73. doi: 10.1111/j.1365-2567.2008.02878.x. Epub 2008 Jun 13.


Interleukin-15 (IL-15) is a proinflammatory cytokine that is overexpressed in rheumatoid arthritis (RA), a disease characterized by activation of monocytes/macrophages (MPhi), and by expansion of autoreactive CD4(+) T cells. We hypothesized that IL-15 plays a major role for this expansion of CD4(+) T cells and modulates the phenotype of monocytes/MPhi and their interaction with CD4(+) T cells. Here, we show that IL-15 enhances the proliferation of CD4(+) T cells from patients with RA in peripheral blood mononuclear cell cocultures. To further dissect the underlying mechanisms, we employed MPhi from IL-15(-/-) or IL-15 transgenic mice. These were induced to differentiate or were stimulated with IL-15. Here we show that addition of IL-15 during differentiation of MPhi (into 'IL-15MPhi') and overexpression of IL-15 by MPhi from IL-15(tg) mice leads to increased levels of major histocompatibility complex class II expression. This resulted in enhanced stimulation of antigen-specific CD4(+) T cells in vitro and was accompanied by reduced messenger RNA expression in MPhi for immunosuppressive SOCS3. The proliferation rates of IL-15MPhi and IL-15(tg)MPhi were high, which was reflected by increased p27(Kip1) and reduced p21(Waf1) levels. In view of high serum and synovial levels of IL-15 in patients with RA, our data suggest the possibility that this excess IL-15 in RA may stimulate monocytes/MPhi to activate the characteristic autoreactive CD4(+) T cells in RA.

MeSH terms

  • Aged
  • Animals
  • Antigen Presentation / immunology
  • Arthritis, Rheumatoid / immunology*
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Cycle Proteins / metabolism
  • Cell Differentiation / immunology
  • Cell Proliferation
  • Cells, Cultured
  • Coculture Techniques
  • Female
  • Histocompatibility Antigens Class II / metabolism
  • Humans
  • Interleukin-15 / immunology*
  • Lymphocyte Activation / immunology
  • Macrophage Activation / immunology
  • Macrophages / immunology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Middle Aged
  • Phagocytosis / immunology
  • Receptors, Interleukin-15 / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction / methods


  • Cell Cycle Proteins
  • Histocompatibility Antigens Class II
  • Interleukin-15
  • Receptors, Interleukin-15